The proposed research project studies the relationships of altered myoinositol metabolism in peripheral nerve to insulin deficiency and to nerve conduction impairment. We will employ several newly-developed and metabolically-defined in vitro tissue preparations to explore the effects of experimental diabetes on various pathways of myoinositol metabolism in peripheral nerve. Experimental diabetes in the rat and rabbit impairs motor nerve conduction velocity (MNCV) and is associated with a reduction in the normal 90-fold tissue-to-plasma concentration gradient of myoinositol in peripheral nerve. The conduction impairment in the rat is reversed or prevented if the fall in tissue myoinositol is corrected. Neither the mechanisms responsible for the high tissue myoinositol levels nor their biochemical function are known. As a consequence, the mechanisms by which experimental diabetes reduces nerve myoinositol and secondarily impairs MNCV are entirely unclear, but may have important relevance to human diabetic neuropathy. In Phase I of our studies, will consider the mechanism(s) by which experimental insulin deficiency and/or hyperglycemia reduce the concentration of free myoinositol in peripheral nerve. Preliminary data suggest that active concentration myoinositol occurs in peripheral nerve and is competively inhibited by high physiologic glucose concentrations. We intend to explore this mechanism and other potential mechanisms by which experimental diabetes might impair nerve myoinositol concentration. In Phase II, we will begin to consider the mechanism(s) by which altered tissue myoinositol metabolism deranges peripheral nerve function. We will study several metabolic derangements characteristics of in vitro nerve preparations from diabetic animals to determine which are normalized by prevention of the accompanying fall in tissue myoinositol. Since MNCV is also normalized, we propose that only metabolic defects which arelikewise normalized should be considered potential metabolic causes of impaired MNCV in experimental diabetes. Those selected metabolic defects will be pursued in further, more-detailed studies.